Hepatocellular cancer (HCC) is among the most common and most lethal adult cancers worldwide, and is increasing in prevalence in the United States. Over 70% of human hepatocarcinomas express mutant thyroid hormone receptors (TRs). Wild-type TRs function as hormone-regulated transcription factors. We propose to determine the role of the TR mutations associated with hepatocarcinoma in the establishment or progression of these neoplasia. From characterizations in vitro, we know that virtually all of the HCC mutant TRs tested function as dominant-negative inhibitors of wild-type TR function, and that wild-type TRs exert growth suppressive effects in cultured cells that are abrogated by at least certain of the mutant TRs found in HCCs. We now seek to directly examine the role of these HCC TR mutants in oncogenesis in vivo in a transgenic model. Specific aim 1. We will create transgenic mouse lines expressing either wild-type TRalphal or a TRalphal mutant first isolated from a human HCC. Several independent founders will be obtained for each transgenic allele and analyzed. Transgenic mouse lines displaying comparable levels of expression of wild-type and HCC mutant TRs, together with unmodified control mice, will be employed for specific aim 2. Specific aim 2. We will analyze the unmodified and transgene lines for incidence, progression, and type of neoplasia. We are particularly interested in determining if the transgenic strains display altered rates, progression, or presentation of HCC compared to unmodified mice. We will use both a spontaneous and a chemically-induced HCC protocol to investigate the effects of the transgene as an initiator and as a modifier of the neoplastic program. Specific aim 3. We will expand our transgenic study to additional TR mutants associated with HCC, and compare their actions to those of TR mutants associated with other neoplastic or endocrine disorders. Relevance: Alterations in thyroid hormone receptors occur at high frequency in human liver tumors. Our proposed experiments seek to improve our understanding of the basis behind this phenomenon, and may suggest improvements in the treatment of these human cancers.